Insulin resistance is a key pathophysiologic feature of the metabolic syndrome and is strongly associated with co-existing cardiovascular risk factors and accelerated atherosclerosis. Nutritional supplementation with the use of botanicals that effectively increase insulin sensitivity represent a very attractive and novel approach for future studies designed to intervene in the development of metabolic syndrome. Unfortunately, considerable controversy exists regarding the effect of botanical supplements on the metabolic syndrome as there is a paucity of data in humans in regard to the effect of botanicals to improve measures of insulin action in vivo or on cellular aspects of insulin action. However, we have demonstrated that a well characterized extract of Artemisia dracunculus L. regulates insulin receptor signaling at the cellular level, increases insulin sensitivity in vivo, and have identified novel proteins and several intracellular pathways modulated by the extract. Specifically, our studies have demonstrated that the mechanism by which A. dracunulus L. regulates insulin action at the cellular level may be secondary to modulating negative regulators of insulin receptor signaling, i.e. protein-tyrosine phosphatases, and reducing lipid intermediates in target tissues. For the next funding cycle, investigations will be expanded in two areas. First, we will include other selected members of the Artemisia genus representing both closely and distantly related species since it remains unclear how their diverse biochemical and taxonomical characteristics are related. Secondly, with use of state of the art metabolomic profiling and proteomic techniques, we will significantly expand investigations to provide in-depth and comprehensive analysis of the cellular mechanisms of action operative in vivo by which extracts of Artemisia sp. improve insulin sensitivity. Thus, the primary objective is to evaluate the combined effects of selected Artemisia sp. extracts to enhance and modify cellular lipid metabolism while simultaneously modulating negative regulators of insulin receptor signaling, i.e. PTPases, in skeletal muscle and liver as complementary components of the mechanism by which these botanicals enhance insulin sensitivity and attenuate the progression to metabolic syndrome.